Epithelial inflammation resulting from an inherited loss-of-function mutation in EGFR.
Epithelial inflammation resulting from an inherited loss-of-function mutation in EGFR.
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DOI：
10.1038/jid.2014.164
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发表时间：
2014-10
影响因子：
6.5
通讯作者：
McGrath, John A.
中科院分区：
文献类型：
--
作者：
Campbell, Patrick;Morton, Penny E.;Takeichi, Takuya;Salam, Amr;Roberts, Nerys;Proudfoot, Laura E.;Mellerio, Jemima E.;Aminu, Kingi;Wellington, Cheryl;Patil, Sachin N.;Akiyama, Masashi;Liu, Lu;McMillan, James R.;Aristodemou, Sophia;Ishida-Yamamoto, Akemi;Abdul-Wahab, Alya;Petrof, Gabriela;Fong, Kenneth;Harnchoowong, Sarawin;Stone, Kristina L.;Harper, John I.;McLean, W. H. Irwin;Simpson, Michael A.;Parsons, Maddy;McGrath, John A.
表皮生长因子受体 (EGFR) 信号传导通过 EGFR/配体相互作用刺激多种信号转导途径，对于组织稳态至关重要。据报道，炎症和恶性疾病中存在异常 EGFR 信号传导，但迄今为止尚未记录到 EGFR 的原发性遗传缺陷。通过全外显子组测序，我们在一名患有影响皮肤、肠道和肺部的终生炎症的男婴中发现了 EGFR 纯合性功能丧失错义突变（c.1283G>A；p.Gly428Asp）。在出生的第一年，他的皮肤出现糜烂、干鳞和脱发。随后，出现了许多丘疹和脓疱——类似于接受 EGFR 抑制剂药物的患者中出现的皮疹。皮肤活检显示表皮中 EGFR 的细胞分布发生改变，细胞膜标记减少，突变受体的体外分析显示 EGFR 磷酸化和 EGF 刺激的下游信号传导被消除。对患者皮肤的微阵列分析强调了角质形成细胞的分化紊乱/过早终末分化以及几种炎症/先天免疫反应网络的上调。这名男孩死于广泛的皮肤和胸部感染以及电解质失衡，享年 2.5 岁。该病例强调了 EGFR 信号消融后上皮功能障碍的主要机制，并说明了 EGFR 抑制对其他组织的更广泛影响。
Epidermal growth factor receptor (EGFR) signaling is fundamentally important for tissue homeostasis through EGFR/ligand interactions that stimulate numerous signal transduction pathways. Aberrant EGFR signaling has been reported in inflammatory and malignant diseases but thus far no primary inherited defects in EGFR have been recorded. Using whole-exome sequencing, we identified a homozygous loss-of-function missense mutation in EGFR (c.1283G>A; p.Gly428Asp) in a male infant with life-long inflammation affecting the skin, bowel and lungs. During the first year of life, his skin showed erosions, dry scale, and alopecia. Subsequently, there were numerous papules and pustules – similar to the rash seen in patients receiving EGFR inhibitor drugs. Skin biopsy demonstrated an altered cellular distribution of EGFR in the epidermis with reduced cell membrane labeling, and in vitro analysis of the mutant receptor revealed abrogated EGFR phosphorylation and EGF-stimulated downstream signaling. Microarray analysis on the patient’s skin highlighted disturbed differentiation/premature terminal differentiation of keratinocytes and upregulation of several inflammatory/innate immune response networks. The boy died aged 2.5 years from extensive skin and chest infections as well as electrolyte imbalance. This case highlights the major mechanism of epithelial dysfunction following EGFR signaling ablation and illustrates the broader impact of EGFR inhibition on other tissues.
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影响因子：
64.8
作者：
MIETTINEN, PJ;BERGER, JE;DERYNCK, R
通讯作者：
DERYNCK, R
影响因子：
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Macia, Eric;Ehrlich, Marcelo;Kirchhausen, Tomas
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Kirchhausen, Tomas
影响因子：
6.5
作者：
Repertinger, SK;Campagnaro, E;Hansen, LA
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Hansen, LA
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17.1
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Mascia F;Lam G;Keith C;Garber C;Steinberg SM;Kohn E;Yuspa SH
通讯作者：
Yuspa SH
影响因子：
64.5
作者：
Ogiso, H;Ishitani, R;Yokoyama, S
通讯作者：
Yokoyama, S